Submissions for variant NM_000179.3(MSH6):c.1135_1139del (p.Arg378_Arg379insTer)

dbSNP: rs267608077

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074635	SCV000107835	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000129834	SCV000184650	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	The c.1135_1139delAGAGA pathogenic mutation (also known as p.R379*), located in coding exon 4 of the MSH6 gene, results from a deletion of 5 nucleotides at nucleotide positions 1135 to 1139. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been previously identified in an individual diagnosed with Lynch syndrome (Kets CM et al. Br. J. Cancer. 2006 Dec 18;95(12): 1678-82) and in a patient with CMMRD (Tesch VK et al. Front Immunol. 2018 Jul;9:1506). It has also been reported in an individual with breast cancer at age 60, as well as endometrial and ovarian cancer at age 61, whose endometrial tumor showed loss of MSH2 on IHC (Frolova AI et al. Gynecol. Oncol. 2015 Apr;137:7-13). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000202120	SCV000211383	pathogenic	not provided	2023-02-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Kets et al., 2006; Frolova et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 28888541, 17117178, 17453009, 25617771, 26681312, 26845104, 27064304, 28152038, 28452373, 26689913, 28514183, 29625052, 30787465, 30013564)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074635	SCV000266088	pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000504011	SCV000595850	pathogenic	Lynch syndrome 5	2016-08-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129834	SCV000685168	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with colorectal cancer (PMID: 17117178), endometrial and/or ovarian cancer (PMID: 17453009, 26845104, 25617771), and cervical cancer (PMID: 26681312). This variant has been identified in 1/250986 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629947	SCV000750903	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg379*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs777907133, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with colorectal polyps, endometrial cancer, and cervical cancer (PMID: 17117178, 25617771, 26681312, 26845104, 28514183). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993788	SCV000917791	pathogenic	Hereditary nonpolyposis colon cancer	2024-02-21	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1135_1139delAGAGA (p.Arg379X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 250986 control chromosomes (gnomAD). c.1135_1139delAGAGA has been reported in the literature in individuals affected with Lynch Syndrome and Lynch Syndrome-associated malignancies (e.g. Kets_2006, Shirts_2015, Susswein_2015, Frolova_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17117178, 26681312, 25617771, 26845104). ClinVar contains an entry for this variant (Variation ID: 89174). Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202120	SCV001469563	pathogenic	not provided	2019-09-25	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH6 protein synthesis. In the published literature, it has been reported in individuals affected with endometrial, ovarian, and breast cancer (PMID: 17117178 (2006), 17453009 (2007), 25617771 (2015), 26681312 (2015)), as well as in a compound heterozygous individual with CMMRD syndrome (PMID: 30013564 (2018)). Based on the available information, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000202120	SCV001747257	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV002463634	SCV002758553	pathogenic	Lynch syndrome 1	2022-08-01	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PM2, PS4
Human Genetics Bochum, Ruhr University Bochum	RCV000504011	SCV002758577	pathogenic	Lynch syndrome 5	2022-08-01	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PM2
Myriad Genetics, Inc.	RCV000504011	SCV004188185	pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003460657	SCV004195799	pathogenic	Endometrial carcinoma	2023-05-07	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000074635	SCV005045713	pathogenic	Lynch syndrome	2023-09-22	criteria provided, single submitter	clinical testing	The c.1135_1139del (p.Arg379*) variant in the MSH6 gene, that encodes for mutS homolog 6, introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in several individuals (>10) affected with endometrial, ovarian, breast, colorectal cancers and Lynch syndrome (PMID:17117178, 17453009, 25617771, 28452373, 28514183, 26681312). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 9354786, 11709755, 20028993, 25318681). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 29345684, 28514183) and by several ClinVar submitters (ClinVar ID: 418928, 1172098, 183736, 89184). This variant is found to be rare (1/250986; 0.000003984) in the general population database, gnomAD and interpreted as pathogenic by several ClinVar submitters including the expert panel (ClinVar ID: 89174). Therefore, the c.1135_1139del (p.Arg379*) variant in the MSH6 gene is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000074635	SCV005429258	pathogenic	Lynch syndrome	2024-08-31	criteria provided, single submitter	clinical testing	The c.1135_1139del (p.Arg379*) variant in the MSH6 gene, that encodes for mutS homolog 6, introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in several individuals (>10) affected with endometrial, ovarian, breast, colorectal cancers and Lynch syndrome (PMID:17117178, 17453009, 25617771, 28452373, 28514183, 26681312). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 9354786, 11709755, 20028993, 25318681). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 29345684, 28514183) and by several ClinVar submitters (ClinVar ID: 418928, 1172098, 183736, 89184). This variant is found to be rare (1/250986; 0.000003984) in the general population database, gnomAD and interpreted as pathogenic by several ClinVar submitters including the expert panel (ClinVar ID: 89174). Therefore, the c.1135_1139del (p.Arg379*) variant in the MSH6 gene is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202120	SCV000257205	likely pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202120	SCV001552841	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202120	SCV001742958	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000202120	SCV001808057	pathogenic	not provided		no assertion criteria provided	clinical testing